Superparamagnetic iron oxide nanoparticles for magnetic hyperthermia: recent advancements, molecular effects, and future directions in the omics era

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted attention in the biomedical field thanks to their ability to prompt hyperthermia in response to an alternated magnetic field. Hyperthermia is well known for inducing cell death, in particular in tumour cells, which seem to have a higher sensitivity to temperature increases. For this reason, hyperthermia has been recommended as a therapeutic tool against cancer. Despite the potentialities of this approach, little is still known about the effects provoked by magnetic hyperthermia at the molecular level, and about the particular cell death mechanisms that are activated. Nevertheless, in-depth knowledge of this aspect would allow improvement of therapeutic outcomes and favour clinical translation. Moreover, in the last few decades, a lot of effort has been put into finding an effective delivery strategy that could improve SPION biodistribution and localisation at the action site. The aim of this review is to provide a general outline of magnetic hyperthermia, focusing on iron oxide nanoparticles and their interactions with magnetic fields, as well as on new strategies to efficiently deliver them to the target site, and on recent in vitro and in vivo studies proposing possible cell death pathways activated by the treatment. We will also cover their current clinical status, and discuss the contributions of omics in understanding molecular interactions between iron oxide nanoparticles and the biological environment

Probing the Ultrastructure of Spheroids and Their Uptake of Magnetic Nanoparticles by FIB–SEM

Spheroids are 3D cellular systems largely adopted as model for high-throughput screening of molecules and diagnostics tools. Furthermore, those cellular platforms also represent a model for testing new delivery carries for selective targeting. The coupling between the 3D cell environment and the nanovectors can be explored at the macroscale by optical microscopy. However, the nanomaterial-cell interplay finds major action at the single cell and extracellular matrix level with nanoscale interactions. Electron microscopy offers the resolution to investigate those interactions; however, the specimen preparation finds major drawbacks in its operation time and preciseness. In this context, focused ion beam and scanning electron microscopy (FIB–SEM) allows for fast processing and high resolution of the cell-nanomaterial interface. Here, in fact, a novel approach is shown to prepare large-area 3D spheroid cell culture specimens for FIB–SEM. Sectioning procedures are explored to preserve the peculiar structure of spheroids and their interaction with magnetic nanovectors. The results pave the way for advanced investigations of 3D cellular systems with nano and micromaterials relevant to tissue engineering, bioelectronics, and diagnostics

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

Investigation of interactions between poly-l-lysine-coated boron nitride nanotubes and C2C12 cells: up-take, cytocompatibility, and differentiation

Boron nitride nanotubes (BNNTs) have generated considerable interest within the scientific community by virtue of their unique physical properties, which can be exploited in the biomedical field. In the present in vitro study, we investigated the interactions of poly-l-lysine-coated BNNTs with C2C12 cells, as a model of muscle cells, in terms of cytocompatibility and BNNT internalization. The latter was performed using both confocal and transmission electron microscopy. Finally, we investigated myoblast differentiation in the presence of BNNTs, evaluating the protein synthesis of differentiating cells, myotube formation, and expression of some constitutive myoblastic markers, such as MyoD and Cx43, by reverse transcription – polymerase chain reaction and Western blot analysis. We demonstrated that BNNTs are highly internalized by C2C12 cells, with neither adversely affecting C2C12 myoblast viability nor significantly interfering with myotube formation

Barium titanate nanoparticles and hypergravity stimulation improve differentiation of mesenchymal stem cells into osteoblasts.

BACKGROUND: Enhancement of the osteogenic potential of mesenchymal stem cells (MSCs) is highly desirable in the field of bone regeneration. This paper proposes a new approach for the improvement of osteogenesis combining hypergravity with osteoinductive nanoparticles (NPs). MATERIALS AND METHODS: In this study, we aimed to investigate the combined effects of hypergravity and barium titanate NPs (BTNPs) on the osteogenic differentiation of rat MSCs, and the hypergravity effects on NP internalization. To obtain the hypergravity condition, we used a large-diameter centrifuge in the presence of a BTNP-doped culture medium. We analyzed cell morphology and NP internalization with immunofluorescent staining and coherent anti-Stokes Raman scattering, respectively. Moreover, cell differentiation was evaluated both at the gene level with quantitative real-time reverse-transcription polymerase chain reaction and at the protein level with Western blotting. RESULTS: Following a 20 g treatment, we found alterations in cytoskeleton conformation, cellular shape and morphology, as well as a significant increment of expression of osteoblastic markers both at the gene and protein levels, jointly pointing to a substantial increment of NP uptake. Taken together, our findings suggest a synergistic effect of hypergravity and BTNPs in the enhancement of the osteogenic differentiation of MSCs. CONCLUSION: The obtained results could become useful in the design of new approaches in bone-tissue engineering, as well as for in vitro drug-delivery strategies where an increment of nanocarrier internalization could result in a higher drug uptake by cell and/or tissue constructs

Artificially altered gravity elicits cell homeostasis imbalance in planarian worms, and cerium oxide nanoparticles counteract this effect

Gravity alterations elicit complex and mostly detrimental effects on biological systems. Among these, a prominent role is occupied by oxidative stress, with consequences for tissue homeostasis and development. Studies in altered gravity are relevant for both Earth and space biomedicine, but their implementation using whole organisms is often troublesome. Here we utilize planarians, simple worm model for stem cell and regeneration biology, to characterize the pathogenic mechanisms brought by artificial gravity alterations. In particular, we provide a comprehensive evaluation of molecular responses in intact and regenerating specimens, and demonstrate a protective action from the space-apt for nanotechnological antioxidant cerium oxide nanoparticles

Delivery of thyronamines (TAMs) to the brain: A preliminary study

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property

Cell Membrane-Coated Magnetic Nanocubes with a Homotypic Targeting Ability Increase Intracellular Temperature due to ROS Scavenging and Act as a Versatile Theranostic System for Glioblastoma Multiforme

In this study, hybrid nanocubes composed of magnetite (Fe3O4) and manganese dioxide (MnO2), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 \ub0C) due to the exothermic scavenging reaction of hydrogen peroxide (H2O2) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 \ub5g mL 121 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse